#Mendelian Randomization Analysis: Major Depressive Disorder and Alzheimer's Disease By Dr. Shea Andrews, generated on 2018-09-08
## [1] FALSEData sources
Major Depressive Disorder Wray et al Nature Genet 2018: The Psychiatric Genomics Consortium (PGC) conducted a GWAS meta-analysis across seven cohorts (PGC, deCODE, Generation Scotland, GERA, iPSYCH, UK Biobank, and 23andMe) containing 130,664 MDD cases and 330,470 controls. Participants were of European Ancestry.
Late Onset Alzheimer’s disease Lambert et al 2013: The International Genomics of Alzheimer’s Project (IGAP) is a meta-analysis of 4 previously published GWAS datasets: the European Alzheimer’s Disease Imitative (EADI), the Alzheimer Disease Genetics Consortium (ADGC), Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), and Genetic and Environmental Risk in AD (GERAD) and includes a sample of 17,008 LOAD cases and 37,154 cognitively normal elder controls. Participants in IGAP were of European ancestry, the average age was 71 and 58.4% of participants were women.
Alzheimer’s Age of Onset Surivial Huang et al 2017: A GWAS of age of onset in LOAD was conducted in 14,406 AD case samples and 25,849 control samples from the IGAP using Cox proportional hazard regressions. Participants were of European ancestry, in cases the the average AAO was 74.8 and 61.7% were women, in controls the average AAE was 79.0 and 59.6% were women.
CSF Ab42, tau & ptau Deming et al 2017: A GWAS of CSF AB42, ptau and tau levels (pg/mL) was conducted in 3,146 participants. Participants were of Eurpean ancestry.
Hippocampal Volume Hibar et al 2017: A GWAS of hippocampal volume perfomed in 26,814 (ENIGMA and CHARGE consortiums) individules of European Ancestry discovered 9 independent loci.
Instrumental Variables
LD Clumping: For standard two sample MR it is important to ensure that the instruments for the exposure are independent. LD clumping can be performed using the data_clump function from the TwoSampleMR package, which uses EUR samples from the 1000 genomes project to estimate LD between SNPs and amonst SNPs that have and LD above a given threshold, only the SNP with the lowest p-value will be retained.
Proxy SNPs: SNPs associated with Major Depressive Disorder were extracted from the GWAS of LOAD, AAOS, AB42, ptau and tau. Where SNPs were not available in the outcome GWAS, the EUR thousand genomes was queried to identified potential proxy SNPs that are in linkage disequilibrium (r2 > 0.8) of the missing SNP.
Major Depressive Disorder
Major Depressive Disorder: 270 SNPs (Table 1) were assoicated with were associated with Major Depressive Disorder at p < 5e-6. After LD clumping, 79 of 270 SNPs were removed.
LOAD
Of the the 191 SNPs associated with Major Depressive Disorder, 175 were available in the LOAD GWAS (Table 2).
Table 2: SNPS associated with Major Depressive Disorder avalible in LOAD GWASAAOS
Of the the 191 SNPs associated with Major Depressive Disorder, 191 were available in the AAOS GWAS (Table 3).
Table 3: SNPS associated withAB42
Of the the 191 SNPs associated with Major Depressive Disorder, 135 were available in the CSF AB42 GWAS (Table 4).
Table 4: SNPS associated with Major Depressive Disorder avalible in ab42 GWASPtau
Of the the 191 SNPs associated with Major Depressive Disorder, 148 were available in the CSF Ptau GWAS (Table 5).
Table 5: SNPS associated with Major Depressive Disorder avalible in Ptau GWASTau
Of the the 191 SNPs associated with Major Depressive Disorder, 135 were available in the CSF Tau GWAS (Table 6).
Table 6: SNPS associated with Major Depressive Disorder avalible in tau GWASHippocampal volume
Of the the 191 SNPs associated with Major Depressive Disorder, 187 were available in the Hippocampal volume (Table 7).
Table 7: SNPS associated with Major Depressive Disorder avalible in Hippocampal volume GWASData harmonization
Harmonize the exposure and outcome datasets so that the effect of a SNP on the exposure and the effect of that SNP on the outcome correspond to the same allele. The harmonise_data function from the TwoSampleMR package can be used to perform the harmonization step, by default it try’s to infer the forward strand alleles using allele frequency information. EAF were not availbe in the IGAP summary statisitics, as such the allele frequencies reported in the AAOS anaylsis were used.
Major Depressive Disorder ~ LOAD
Table 8: Harmonized Major Depressive Disorder and LOAD datasetsMajor Depressive Disorder ~ AAOS
Table 9: Harmonized Major Depressive Disorder and AAOS datasetsMajor Depressive Disorder ~ AB42
Table 10: Harmonized Major Depressive Disorder and AB42 datasetsMajor Depressive Disorder ~ Ptau
Table 11: Harmonized Major Depressive Disorder and Ptau datasetsMajor Depressive Disorder ~ Tau
Table 12: Harmonized Major Depressive Disorder and Tau datasetsMajor Depressive Disorder ~ Hippocampal Volume
Table 13: Harmonized Major Depressive Disorder and Hippocampal Volume datasets
Pleiotropy
Pleiotropy was assesed using Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), that allows for the evlation of evaluation of horizontal pleiotropy in a standared MR model. MR-PRESSO performs a global test for detection of horizontal pleiotropy and correction of pleiotropy via outlier removal.
Major Depressive Disorder ~ LOAD: The MR-PRESSO global test for pleiotropy was non-significant
Major Depressive Disorder ~ AAOS: The MR-PRESSO global test for pleiotropy was non-significant.
Major Depressive Disorder ~ AB42: The MR-PRESSO global test for pleiotropy was significant (p = 0.0364).. The following SNPs were removed due to pleiotropy: No significant outliers
Major Depressive Disorder ~ Ptau: The MR-PRESSO global test for pleiotropy was non-significant.
Major Depressive Disorder ~ Tau: The MR-PRESSO global test for pleiotropy was non-significant..
Major Depressive Disorder ~ hippocampal volume: The MR-PRESSO global test for pleiotropy was non-significant
Mendelian Randomization Analysis
To obtain an overall estimate of causal effect, the SNP-exposure (Major Depressive Disorder) and SNP-outcome coefficients (Alzheimer’s disease and Alzheimer’s Age of Onset) were combined in 1) a random-effects meta-analysis using an inverse-variance weighted approach (IVW); 2) a Weighted Median approach; 3) and Egger Regression. IVW is equivalent to a weighted regression of the SNP-outcome coefficients on the SNP-exposure coefficients with the intercept constrained to zero. This method assumes that all variants are valid instrumental variables based on the Mendelian randomization assumptions. The causal estimate of the IVW analysis expresses the causal increase in the outcome (or log odds of the outcome for a binary outcome) per unit change in the exposure. Weighted median MR allows for 50% of the instrumental variables to be invalid. MR-Egger regression allows all the instrumental variables to be subject to direct effects (i.e. horizontal pleiotropy), with the intercept representing bias in the causal estimate due to pleiotropy and the slope representing the causal estimate.
Major Depressive Disorder ~ LOAD
Figure 1 illustrates the SNP-specific associations with Major Depressive Disorder versus the association between each SNP and risk of LOAD.
Fig. 1: Scatterplot of SNP effects for the association of Trait and LOAD
Figure 2 and Table 1 shows the SNP-specific effects and overall IVW, weighted median and Egger regression causal estimates of genetically predicted Major Depressive Disorder on risk of LOAD.
Fig. 2: Forrest plot of Wald ratios and 95% CIs for SNP-specific and overall IVW, Weighted median and Egger associations
Figure 3 shows a funnel plot to detect pleiotropy and Table 2 show the results of Cochrans Q heterogeneity test to assess for the presence of pleiotropy.
Fig. 3: Funnel plot of the Trait – LOAD causal estimates against their precession
Major Depressive Disorder ~ AAOS
Figure 4 illustrates the SNP-specific associations with Major Depressive Disorder versus the association between each SNP and AAOS.
Fig. 4: Scatterplot of SNP effects for the association of Trait and AAOS
Figure 5 and Table 4 shows the SNP-specific effects and overall IVW, weighted median and Egger regression causal estimates of genetically predicted Major Depressive Disorder on AAOS.
Fig. 5: Forrest plot of Wald ratios and 95% CIs for SNP-specific and overall IVW, Weighted median and Egger associations
Figure 6 shows a funnel plot to detect pleiotropy and Table 5 show the results of Cochrans Q heterogeneity test to assess for the presence of pleiotropy.
Fig. 6: Funnel plot of the traitohol Conumption – AAOS causal estimates against their precession
Major Depressive Disorder ~ AB42
Figure 1 illustrates the SNP-specific associations with Major Depressive Disorder versus the association between each SNP and AB42.
Fig. 1: Scatterplot of SNP effects for the association of trait and AB42
Figure 2 and Table 7 shows the SNP-specific effects and overall IVW, weighted median and Egger regression causal estimates of genetically predicted Major Depressive Disorder CSF AB42 levels.
Fig. 2: Forrest plot of Wald ratios and 95% CIs for SNP-specific and overall IVW, Weighted median and Egger associations
Figure 3 shows a funnel plot to detect pleiotropy and Table 8 show the results of Cochrans Q heterogeneity test to assess for the presence of pleiotropy.
Fig. 3: Funnel plot of the trait – AB42 causal estimates against their precession
Major Depressive Disorder ~ Ptau
Figure 1 illustrates the SNP-specific associations with Major Depressive Disorder versus the association between each SNP and risk of Ptau.
Fig. 1: Scatterplot of SNP effects for the association of trait and Ptau
Figure 2 and Table 9 shows the SNP-specific effects and overall IVW, weighted median and Egger regression causal estimates of genetically predicted Major Depressive Disorder on risk of Ptau.
Fig. 2: Forrest plot of Wald ratios and 95% CIs for SNP-specific and overall IVW, Weighted median and Egger associations
Figure 3 shows a funnel plot to detect pleiotropy and Table 10 show the results of Cochrans Q heterogeneity test to assess for the presence of pleiotropy.
Fig. 3: Funnel plot of the trait – Ptau causal estimates against their precession
Major Depressive Disorder ~ Tau
Figure 1 illustrates the SNP-specific associations with Major Depressive Disorder versus the association between each SNP and CSF Tau levels.
Fig. 1: Scatterplot of SNP effects for the association of trait and Tau
Figure 2 and Table 12 shows the SNP-specific effects and overall IVW, weighted median and Egger regression causal estimates of genetically predicted Major Depressive Disorder on risk of Tau.
Fig. 2: Forrest plot of Wald ratios and 95% CIs for SNP-specific and overall IVW, Weighted median and Egger associations
Figure 3 shows a funnel plot to detect pleiotropy and Table 13 show the results of Cochrans Q heterogeneity test to assess for the presence of pleiotropy.
Fig. 3: Funnel plot of the trait – Tau causal estimates against their precession
Major Depressive Disorder ~ HV
Figure 1 illustrates the SNP-specific associations with Major Depressive Disorder versus the association between each SNP and hippocampal volume.
Fig. 1: Scatterplot of SNP effects for the association of trait and hippocampal volume
Figure 2 and Table 12 shows the SNP-specific effects and overall IVW, weighted median and Egger regression causal estimates of genetically predicted Major Depressive Disorder on risk of hippocampal volume.
Fig. 2: Forrest plot of Wald ratios and 95% CIs for SNP-specific and overall IVW, Weighted median and Egger associations
Figure 3 shows a funnel plot to detect pleiotropy and Table 13 show the results of Cochrans Q heterogeneity test to assess for the presence of pleiotropy.
Fig. 3: Funnel plot of the trait – hippocampal volume causal estimates against their precession